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The Role of MUC5B Salivary Mucin in Modulating Oral Bacterial Surface Colonization and Interspecies Competition

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The Role of MUC5B Salivary Mucin in Modulating Oral Bacterial Surface Colonization and Interspecies Competition The Role of MUC5B Salivary Mucin in Modulating Oral Bacterial Surface Colonization and Interspecies Competition The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:40046419 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA The role of MUC5B salivary mucin in modulating oral bacterial surface colonization and interspecies competition A dissertation presented by Erica Shapiro Frenkel to The Department of Biological Sciences in Dental Medicine in partial fulfillments of the requirements for the degree of Doctor of Philosophy in the subject of Biological Sciences in Dental Medicine Harvard University Cambridge, Massachusetts March 2017 © 2017 Erica Shapiro Frenkel All rights reserved Dissertation Advisor: Katharina Ribbeck Erica Shapiro Frenkel The role of MUC5B salivary mucin in modulating oral bacterial surface colonization and interspecies competition Abstract Mucus acts as a protective barrier on wet epithelial surfaces in the body including the gastrointestinal, respiratory, and reproductive tracts. A main component of mucus is mucin, which give mucus its viscoelastic properties and is a key component of host defense at these epithelial interfaces. Altered mucin production has been linked to gastrointestinal diseases such as Crohn’s disease and respiratory illnesses like cystic fibrosis, which highlights the importance of regulated mucin production. Although the role of mucins in gastrointestinal and respiratory illnesses has been well characterized, little is known about how salivary mucins protect the oral cavity from common diseases such as dental caries. Streptococcus mutans is one of the primary bacteria that cause dental caries, which form when bacteria grow on tooth surfaces then produce organic acids as metabolic byproducts. The decrease in local pH leads to dissolution of tooth enamel then cavity formation. The research in this thesis uses purified human MUC5B salivary mucin to better understand how this mucin could play a role in the prevention of cavity formation. Results shown in Chapter 2 demonstrate that MUC5B significantly reduces S. mutans attachment and biofilm formation on glass and hydroxyapatite. In addition, MUC5B does not significantly reduce S. mutans viability indicating the decrease in S. mutans surface colonization is due to a shift in cells from the biofilm to the planktonic state. In Chapter 3, a dual-species competition iii model is used to study the effects of MUC5B in a more complex environment. The two species in the model are S. mutans and Streptococcus sanguinis, which are known to compete in the oral cavity. In this study, MUC5B increases S. mutans and S. sanguinis coexistence. The reduction in interspecies competition could be caused by an increase in the relative proportion of cells in the less competitive planktonic state, which occurs in the presence of MUC5B. Taken together, the results presented in this thesis indicate that MUC5B could play a key role in protecting the oral cavity from disease and in maintaining a healthy microbiota. iv Table of Contents Title page……………………………………………………………………………………....…..i Copyright page………………………………………………………………………………….....ii Abstract…………………………………………………………………………………………...iii Table of Contents………………………………………………………………………………….v Acknowledgements……………………………………………………………………………….vi List of Figures…………………………………………………………………………………...viii Chapter I: Introduction………………………………………………………………...…………..1 Chapter II: Salivary Mucins Protect Surfaces from Colonization by Cariogenic Bacteria……...27 Chapter III: Salivary Mucins Promote the Coexistence of Competing Oral Bacterial Species….47 Chapter IV: Conclusions and Future Directions………………………………………………....63 v Acknowledgments I would like to thank my advisor, Dr. Katharina Ribbeck, for her continual support and guidance throughout my time in her lab. She has been a wonderful mentor whose patience and encouragement allowed me to grow as a scientist and discover the world of microbiology. Words cannot express my gratitude and appreciation. I owe a huge thank you to the Ribbeckers who have always been there for me and were truly the best labmates I could possibly imagine. Julia and Nicole K., thank you for teaching me microbiology. Both of you were especially important in my early days in the lab when I thought that chemistry was the only science I would ever need to know. Wes and Tahoura, thank you for always being there to grab coffee and making time whenever I needed to chat. Nicole B., Thomas, Leon, Brad, Jacob, Gerardo, Caroline, Emi, Kelsey, and Ben, -- thank you. A special thank you to Kate and Tahoura for providing feedback on my thesis drafts. My advisory committee members, Dr. Otto Cordero, Dr. Margaret Duncan and Dr. Max Goodson deserve a special thanks for their helpful suggestions. Also, I would like to thank my dissertation advisory committee, Dr. Margaret Duncan, Dr. Phil Stashenko, Dr. Alan Grodzinsky, and Dr. Abigail Sloan Devlin, for their time and comments. I am grateful to the directors of the Biological Sciences in Dental Medicine program, Dr. Bjorn Olsen and Dr. Yingzi Yang, for their encouragement. This journey would not have been possible without the love and support I received from my family. To my Mom, Dad and brother who always helped me over the obstacles and were there to cheer for me when I succeeded, thank you. And, of course, to Eran, who always understands, knows exactly what to say and has an unwavering belief in my ability to succeed. vi You are truly the best. Lina, thank you for never letting me forget that life is just too short to sweat the small stuff. vii List of Figures Figure 1.1 Mucin dysregulation in disease. Figure 1.2 Introduction to mucins. Figure 1.3 Potential mechanisms by which MUC5B protects the oral cavity from microbial colonization. Figure 1.4 Mucins reduce C. albicans hyphae formation. Figure 2.1 Sucrose enhances S. mutans attachment and biofilm formation. Figure 2.2 Supplemental sugar alters S. mutans growth. Figure 2.3 Salivary mucins reduce S. mutans attachment and biofilm formation. Figure 2.4 S. mutans growth is unaffected by the presence of salivary mucins. Figure 2.5 S. mutans survival is unaffected by salivary mucins. Figure 2.6 Summary of conclusions. Figure 3.1 MUC5B promotes S. mutans and S. sanguinis coexistence. Figure 3.2 At high cell density, S. sanguinis viability decreases over time due to self-killing. Figure 3.3 Methylcellulose does not affect S. mutans and S. sanguinis coexistence. Figure 3.4 MUC5B reduces S. mutans and S. sanguinis surface attachment by shifting cells into the planktonic state. viii Chapter I Introduction Parts of the text presented in this chapter were published in: Frenkel ES, Ribbeck K. 2015. Salivary mucins in host defense and disease prevention. J Oral Microbiol 7:29759. 1 Introduction Mucins, the primary gel-forming component of mucus, provide a critical layer of protection on wet epithelial surfaces in the body including the gastrointestinal tract, female genital tract and respiratory tract. The importance of regulated mucin production in maintaining health is illustrated most clearly by studying the disease states that develop when mucin is dysregulated. Several studies have utilized knockout mice to more specifically characterize the changes that occur when mucins are not present. Mice lacking the Muc2 intestinal mucin showed signs of reduced health compared to wild type mice including increased inflammation in the distal colon, weight loss and mucosal thickening (Figure 1.1A and B) (1, 2). The authors postulate that thickening of the mucosa could be caused by a thinning of the mucus layer, which results in an increase in bacteria contacting the intestinal surface (Figure 1.1A) (1, 3). A separate study looking at respiratory function in Muc5b knockout mice showed that Muc5b deficient mice had significantly increased bacterial load in the lungs and middle ear leading to reduced survival compared to wild type mice (Figure 1.1C) (4). In the oral cavity, decreased salivary flow is linked to increased incidence of dental caries, which could be caused by reduced levels of salivary mucins (5, 6). On the other hand, mucin overproduction is associated with diseases such as asthma and cystic fibrosis, where increased mucus secretion leads to narrowing of airways (7– 9). These findings highlight the importance of regulated mucin production, but our understanding of the precise mechanisms by which mucins provide protection in the oral cavity are not well characterized. The goal of this thesis work is to elucidate the function MUC5B plays in protecting the oral cavity using dental caries as a disease model. Streptococcus mutans, one of the primary bacteria responsible for dental caries, creates cavities when it attaches to and grows 2 Figure 1.1 wild type Muc2 -/- A. B. C. 105 0.2 104 0.1 -actin (%) -actin 3 ! 10 CFU lung per to to 0.0 102 Relative mRNA expression expression mRNA Relative wild type Muc2 -/- wild Muc5b -/- type Figure 1.1 Mucin dysregulation in disease. (A) Colon section from wild type and Muc2 -/- mice. Bacteria are stained red and tissue is counterstained with DAPI. Double arrow represents mucus layer above epithelium in wild type mice. Arrow in Muc2 -/- mice mark bacteria. Scale bars are 100 !m. Taken from (3) with permission. Link to copyright license: https://creativecommons.org/licenses/by/4.0/legalcode. (B) TNF-alpha, an inflammatory cytokine, was significantly upregulated in the colon of Muc2 -/- mice compared to wild type mice. P = 0.03. Taken from (1) with permission. (C) Bacterial load in the lungs of wild type and Muc5b -/- mice at 6 months of age. Taken from (4) with permission. 3 on tooth surfaces. Because surface colonization is a key step in the development of caries, I first study the effect of MUC5B on S. mutans attachment, biofilm formation and survival on various surfaces.
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